The following proposal focuses on the mechanisms by which an endothelial cell adhesion molecule associates with cytoplasmic binding partners. Understanding these molecular interactions will lead to new ways to modulate vascular permeability and angiogenesis, key processes in the pathophysiology of various cutaneous disease states. This pilot and feasibility study is designed to define new binding partners for the VE-cadherin cytoplasmic domain, and thereby reveal new interfaces between cadherins and cellular control mechanisms that regulate microvascular permeability. The goal of this proposal is to use a yeast genetic system, the two-hybrid system, to identify novel partners for the VE-cadherin cytoplasmic tail that might be involved in VE-cadherin endocytosis or in other aspects of VE-cadherin regulation. Specifically, novel binding partners for the VE-cadherin cytoplasmic tail will be identified and characterized. The yeast two hybrid system will be used to screen a dermal microvascular endothelial cell cDNA library. Putative binding partners identified using the two hybrid system will be verified using co-localization and co-immunoprecipitation experiments. The results of this study will form the foundation for future studies directed at understanding how VE-cadherin binding partners regulate endothelial functions in the skin.